1. Field of the Invention
This invention relates generally to a computer implemented drug discovery method. More specifically, the disclosed method permits a user to specify a three dimensional representation of an initial molecular fragment, which may be derived from binding data, crystallographic data, modeling data, or any other source, to identify additional molecular fragments having the same or similar three dimensional shape that may be incorporated into a drug molecule. The likely activity a molecule resulting from inclusion of the identified fragment can be predicted using a modified CoMFA technique as taught in U.S. Pat. No. 7,329,222.
2. Description of Related Art
During drug discovery, the final stage of lead optimization, the modification of an existing drug candidate to avoid liabilities ranging from toxicity issues to patent issues, is usually the most challenging and costly. Compounds are synthesized individually in relatively large quantities and may be tested in dozens of experimental assays. Often it is believed that only one fragment or R-group within a candidate structure is susceptible to modification and so the candidate structures are quite similar. Yet there will be thousands of reasonable alternative R-groups, and selection among these candidates will be increasingly effective as the means for predicting their biological affinities become more accurate. In such cases, the identification of molecular fragments similar in shape to molecular fragments derived from a known drug may be used to rank or propose candidate drug molecules. Alternate 3D representations of molecular fragments, such as topomerically aligned fragments, have been developed and have been successfully employed. In particular, the 3D QSAR technique known as Topomeric CoMFA has been highly successful especially when used in conjunction with a Virtual Library. The Topomeric CoMFA approach has been extended to searching and deriving predicted activities from fragments found in heterogeneous database libraries in U.S. patent application Ser. No. 12/045,511 using a fragmentation on-the-fly technique first taught in U.S. Pat. No. 7,330,793. Topomeric CoMFA techniques taught in these patent documents use fragments generated from molecules that have been determined to share activities at the same receptor to identify similarly shaped fragments in either a Virtual Library or heterogenous database library. However, as noted in U.S. Pat. No. 7,329,222 the use of a rule based (topomeric) procedure for aligning molecular fragments that lies at the heart of the Topomeric CoMFA methodology is not always applicable and may result in 3D fragment conformations that do not approximate those assumed by the fragment in an active molecule.
Importantly, there are many cases where it is believed that an alternative geometric alignment, based on knowledge about receptor site geometry gleaned from other sources, such as x-ray studies or ligand binding, might be more useful in computing a 3D QSAR such as CoMFA. For instance various biophysical and biochemical methods may indicate that a receptor binding site may possess particular geometric and chemical features. Alternatively, it may be desirable to seek alignments that overlay fragments from two or more structurally non-congeneric sets that may, for example, be known to bind to the same receptor. In these circumstances an alignment methodology would be advantageous that could align such structurally varied fragments to some user specified geometry or geometries.
The ultimate goal for the use of the present invention in drug discovery is to permit the drug developer to specify the three dimensional characteristics he/she believes are important for drug binding and to use those 3D characteristics to search for and identify appropriately shaped molecular fragments from molecular databases that may be incorporated into a drug design. The likely activity of such a drug may be predicted using the CoMFA technology as taught in U.S. Pat. No. 7,329,222 and further extended in U.S. patent application Ser. No. 12/045,511 where the alignments generated by the methods of the present invention are used in place of the rule based topomeric alignments.